Adverse Drug Reactions of Acetylcholinesterase Inhibitors in Older People Living with Dementia: A Comprehensive Literature Review

Figures & data

Table 1 The Changes in Pharmacokinetics of Acetylcholinesterase Inhibitors Among Older Adults Living with Dementia

Physiologic Changes	Causes of PK Changes			PK Consequences
	Aging Process	Frailty	Dementia
Reduction in Gl mobility^Citation86,Citation90	✓✓	✓✓		Increased in mean Tmax of donepezil
Reduction in splanchnic blood flow^Citation86,Citation90	✓✓			Increased in mean Tmax of donepezil
Reduction in tissue blood perfusion^Citation190	✓✓			Reduction in rivastigmine’s absorption via skin
Atrophy of epidermis and dermis^Citation190	✓✓			Reduction in rivastigmine’s absorption via skin
Reduction in serum albumin^Citation88,Citation90,Citation193^–^Citation196	✓✓	✓✓	✓✓	Increased free fraction in plasma of high-protein binding AChEI (donepezil)
Reduction in hepatic mass and size^Citation88,Citation89,Citation91,Citation111,Citation112,Citation201^–^Citation205	✓✓			Reduced first-pass metabolism (phase I) and hepatic clearance of donepezil, galantamine and rivastigmine
Increased of inflammatory process^Citation198^–^Citation200		✓✓ Reduced phase II metabolism		Downregulation in metabolism and transporter pathway of donepezil, galantamine and rivastigmine

Abbreviations: PK, pharmacokinetics; PD, pharmacodynamics; AChEI, acetylcholinesterase inhibitor; GI, gastrointestinal; T_max, Time to maximum serum concentration.

Table 2 The Changes in Pharmacokinetics and Pharmacodynamics of Acetylcholinesterase Inhibitors Among Older Adults Living with Dementia

Physiologic Changes	Causes of PK or PD Changes			PK Consequences
	Aging Process	Frailty	Dementia
Reduction in hepatic blood flow^Citation88,Citation89,Citation91,Citation111,Citation112,Citation201^–^Citation205	✓✓			Increased half-life of donepezil, galantamine and rivastigmine
Reduction in renal blood flow^Citation138,Citation208,Citation210,Citation211	✓✓			Reduced renal clearance of donepezil, galantamine and rivastigmine
Reduction in number of nephron^Citation138,Citation208,Citation210,Citation211	✓✓			Increased half-life of donepezil, galantamine and rivastigmine
Reduction in glomerular infiltration rate^Citation138,Citation208,Citation210,Citation211	✓✓	✓✓		Increased half-life of donepezil, galantamine and rivastigmine
Physiologic changes				PD consequences
Micro-disruption of BBB^Citation43,Citation101,Citation102,Citation181,Citation182,Citation215	✓✓		✓✓	Increased permeability of donepezil, galantamine and rivastigmine across BBB
Reduction in P-gp activity^Citation43,Citation101,Citation102,Citation181,Citation182,Citation215	✓✓		✓✓	Increased permeability of donepezil, galantamine and rivastigmine across BBB
High sensitivity to cholinergic receptor^Citation45,Citation46,Citation216	✓✓			Increased response to donepezil, galantamine and rivastigmine

Abbreviations: PK, pharmacokinetics; PD, pharmacodynamics; BBB, blood-brain barrier; P-gp, P-glycoprotein.

Table 3 Common CYP Enzymes-Mediated Pharmacokinetic Drug Interactions of Acetylcholinesterase Inhibitors in Older Adults Living with Dementia

PK Drug Interactions	CYP2D6	CYP3A4	Outcomes
Strong Inhibitors^Citation138,Citation242,Citation246^–^Citation249	Antidepressants	Antibiotics	Increased plasma concentration of donepezil and galantamine Hypercholinergic outcomes Hypersalivation, abdominal pain, diarrhea, nausea, vomiting
	Bupropion	Erythromycin
	Duloxetine	Antifungal drugs
	Fluoxetine	Fluconazole
	Paroxetine	Ketoconazole
	Sertraline	Antiarrhythmic drugs
	Antiarrhythmic drugs	Amiodarone
	Amiodarone	Antipsychotics
	Antipsychotics	Haloperidol
	Aripiprazole	Antidepressants
	Haloperidol	Sertraline

Abbreviations: PK, pharmacokinetics; CYP, cytochrome P450; CYP2D6, cytochrome P450 2D6; CYP3A4, cytochrome P450 3A4.

Table 4 Common Transporter-Mediated Pharmacokinetic Drug Interactions of Acetylcholinesterase Inhibitors in Older Adults Living with Dementia

Transporter-Mediated PK Drug Interactions	Medications	Outcomes
P-gp inhibitors^Citation250^–^Citation252	Antibiotics	Increased plasma concentration of Donepezil as P-gp substrate Hypercholinergic outcomes hypersalivation, QT prolongation, diarrhea, nausea, vomiting
	Erythromycin
	Azithromycin
	Clarithromycin
	Antifungal drugs
	Itraconazole
	Ketoconazole
	Cardiovascular drugs
	Verapamil
	Carvedilol
	Antiplatelet
	Cilostazol
	Ticagrelor
P-gp inducers^Citation250^–^Citation252	Anticonvulsants	Decreased plasma concentration of Donepezil as P-gp substrate
	Carbamazepine
	Phenytoin
	Phenobarbital
	Antituberculosis drugs
	Rifampicin

Abbreviations: PK, pharmacokinetics; P-gp, P-glycoprotein.

Table 5 Pharmacodynamic Interactions in Older Adults with Dementia

PD Drug Interactions	Interactions	Mechanism Effects	Adverse Outcomes
Anticholinergics + AChEIs^Citation138,Citation243,Citation253,Citation254	Antagonistic	Decreased acetylcholine in CNS	Constipation, delirium, cognitive impairment, urinary retention Antagonized the effects of AChEIs
Cholinomimetics or cholinergic agonists + AChEIs^Citation255^–^Citation257	Synergistic	Increased acetylcholine in PNS	Hypersalivation, abdominal pain, diarrhea, nausea, vomiting,
Beta blockers + AChEIs^Citation63,Citation243,Citation261	Synergistic	Decreased sympathetic Increased vagotonic effects	Bradyarrhythmia, heart block, prolonged QT, torsades de pointes syncope
Calcium channel blockers + AChEIs^Citation63,Citation243,Citation261	Synergistic	Decreased sympathetic Increased vagotonic effects	Bradyarrhythmia, heart block, prolonged QT, torsades de pointes, syncope
Antiarrhythmic drugs + AChEIs^Citation63,Citation243,Citation261	Synergistic	Decreased sympathetic Increased vagotonic effects	Bradyarrhythmia, heart block, torsades de pointes, syncope
Antipsychotics + AChEIs^Citation242,Citation243,Citation258,Citation259	Antagonistic	Decreased dopamine in striatum	Rigidity, parkinsonism, worsening of extrapyramidal effects
NSAIDs + AChEIs^Citation136,Citation137,Citation237,Citation243	Synergistic	Increased gastric acid secretion	Gastrointestinal ulcer

Abbreviations: PD, pharmacodynamics; AChEIs, acetylcholinesterase inhibitors; NSAIDs, non-steroidal anti-inflammatory drugs; CNS, central nervous system; PNS, peripheral nervous system.

Table 6 Prevention Strategies for Adverse Drug Reactions of Acetylcholinesterase Inhibitors

Medication Problems	Management
DDIs^Citation47,Citation238,Citation272^–^Citation275,Citation277,Citation280,Citation281	Evaluate drug interactions via application (Micromedex) Evaluate drug-disease interactions by Beers Criteria
Poor compliance^Citation47,Citation272^–^Citation275,Citation282^–^Citation288	Easily understandable drug labels Use simplest regimens Encourage memory techniques (alarm clock, calendar) Evaluate health literacy (language, education, dementia)
Polypharmacy^Citation47,Citation272^–^Citation275	Comprehensive medication review Minimize number of physicians and hospital visits Prescribe only necessary medications
The discontinuation of AChEIs^Citation268	Weighting the risks and the benefits of continuous AChEIs use Consider deprescribing AChEIs in patients with lack of treatment response, severe cognitive function, significantly impaired functional status
PIMs^Citation47,Citation272^–^Citation275,Citation278,Citation279	Comprehensive medication review Evaluate potentially inappropriate medication for older adults with dementia following Beers Criteria
Miscommunication^Citation272^–^Citation275,Citation286^–^Citation288	Evaluate health literacy (language, education, dementia) Ensure the plan with patients and caregivers or family members Encourage technology and technique for older patients to make proper pharmacological plan and management
Age-related physiological changes^Citation47,Citation270,Citation272^–^Citation275	Check physiological problems related to drug administration such as cognitive impairment, visual and auditory problems, and bone-joint deformity
Age-related changes in PK^Citation47,Citation270,Citation272^–^Citation275	Evaluate weight and nutritional status, refers to protein levels Evaluate patients’ hepatic and renal function
Age-related changes in PD^Citation47,Citation270,Citation272^–^Citation275	Start low and slowly titrate AChEIs due to be highly sensitive drug-induced action on cholinergic receptors

Abbreviations: DDIs, drug–drug interactions; PIMs, potentially inappropriate medications; PK, pharmacokinetics; PD, pharmacodynamics; AChEIs, acetylcholinesterase inhibitors.

Heydorn WE. Donepezil (E2020): a new acetylcholinesterase inhibitor. Review of its pharmacology, pharmacokinetics, and utility in the treatment of Alzheimer’s disease. Expert Opin Investig Drugs. 1997;6(10):1527–1535. doi:10.1517/13543784.6.10.1527

 PubMedGoogle Scholar

Ohnishi A, Mihara M, Kamakura H, et al. Comparison of the pharmacokinetics of E2020, a new compound for Alzheimer’s disease, in healthy young and elderly subjects. J Clin Pharmacol. 1993;33(11):1086–1091. doi:10.1002/j.1552-4604.1993.tb01945.x

 PubMed Web of Science ®Google Scholar

Kurz A, Farlow M, Lefèvre G. Pharmacokinetics of a novel transdermal rivastigmine patch for the treatment of Alzheimer’s disease: a review. Int J Clin Pract. 2009;63(5):799–805. doi:10.1111/j.1742-1241.2009.02052.x

 PubMed Web of Science ®Google Scholar

Gauthier S. Acetylcholinesterase inhibitors in the treatment of Alzheimer’s disease. Exp Opin Invest Drugs. 1999;8:1511–1520. doi:10.1517/13543784.8.10.1511

 PubMedGoogle Scholar

Hughes VA, Frontera WR, Wood M, et al. Longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health. J Gerontol a Biol Sci Med Sci. 2001;56(5):B209–217. doi:10.1093/gerona/56.5.B209

 PubMed Web of Science ®Google Scholar

Le Couteur DG, Blyth FM, Creasey HM, et al. The association of alanine transaminase with aging, frailty, and mortality. J Gerontol a Biol Sci Med Sci. 2010;65(7):712–717. doi:10.1093/gerona/glq082

 PubMed Web of Science ®Google Scholar

Tiseo PJ, Rogers SL, Friedhoff LT. Pharmacokinetic and pharmacodynamic profile of donepezil HCl following evening administration. Br J Clin Pharmacol. 1998;46(Suppl 1):13–18. doi:10.1046/j.1365-2125.1998.0460s1013.x

 PubMed Web of Science ®Google Scholar

Coin A, Pamio MV, Alexopoulos C, et al. Donepezil plasma concentrations, CYP2D6 and CYP3A4 phenotypes, and cognitive outcome in Alzheimer’s disease. Eur J Clin Pharmacol. 2016;72(6):711–717. doi:10.1007/s00228-016-2033-1

 PubMed Web of Science ®Google Scholar

Bickel U, Thomsen T, Weber W, et al. Pharmacokinetics of galanthamine in humans and corresponding cholinesterase inhibition. Clin Pharmacol Ther. 1991;50(4):420–428. doi:10.1038/clpt.1991.159

 PubMed Web of Science ®Google Scholar

Bachus R, Bickel U, Thomsen T, Roots I, Kewitz H. The O-demethylation of the antidementia drug galanthamine is catalysed by cytochrome P450 2D6. Pharmacogenetics. 1999;9:661–668. doi:10.1097/00008571-199912000-00001

 PubMedGoogle Scholar

Wynne H. Drug metabolism and ageing. J Br Menopause Soc. 2005;11(2):51–56. doi:10.1258/136218005775544589

 PubMedGoogle Scholar

Butler JM, Begg EJ. Free drug metabolic clearance in elderly people. Clin Pharmacokinet. 2008;47(5):297–321. doi:10.2165/00003088-200847050-00002

 PubMed Web of Science ®Google Scholar

Hubbard RE, O’Mahony MS, Calver BL, Woodhouse KW. Plasma esterases and inflammation in ageing and frailty. Eur J Clin Pharmacol. 2008;64(9):895–900. doi:10.1007/s00228-008-0499-1

 PubMed Web of Science ®Google Scholar

Aitken AE, Richardson TA, Morgan ET. Regulation of drug-metabolizing enzymes and transporters in inflammation. Annu Rev Pharmacol Toxicol. 2006;46:123–149. doi:10.1146/annurev.pharmtox.46.120604.141059

 PubMed Web of Science ®Google Scholar

Full prescription information. Razadyne (galantamine). Available from: https://www.janssenmd.com/pdf/razadyne/PI-Razadyne-RazadyneER.pdf. Assessed November 22, 2020.

 Google Scholar

Fliser D, Zeier M, Nowack R, Ritz E. Renal functional reserve in healthy elderly subjects. J Am Soc Nephrol. 1993;3(7):1371–1377. doi:10.1681/ASN.V371371

 PubMed Web of Science ®Google Scholar

Farlow MR. Clinical pharmacokinetics of galantamine. Clin Pharmacokinet. 2003;42(15):1383–1392. doi:10.2165/00003088-200342150-00005

 PubMed Web of Science ®Google Scholar

Gottwald MD, Rozanski RI. Rivastigmine, a brain-region selective acetylcholinesterase inhibitor for treating Alzheimer’s disease: review and current status. Expert Opin Investig Drugs. 1999;8(10):1673–1682. doi:10.1517/13543784.8.10.1673

 PubMedGoogle Scholar

Mehta DC, Short JL, Hilmer SN, Nicolazzo JA. Drug access to the central nervous system in Alzheimer’s disease: preclinical and clinical insights. Pharm Res. 2015;32(3):819–839.

 PubMed Web of Science ®Google Scholar

Banks WA. Drug delivery to the brain in Alzheimer’s disease: consideration of the blood-brain barrier. Adv Drug Deliv Rev. 2012;64(7):629–639. doi:10.1016/j.addr.2011.12.005

 PubMed Web of Science ®Google Scholar

van Assema DM, Lubberink M, Bauer M, et al. Blood-brain barrier P-glycoprotein function in Alzheimer’s disease. Brain. 2012;135(Pt 1):181–189. doi:10.1093/brain/awr298

 PubMed Web of Science ®Google Scholar

Maher D, Ailabouni N, Mangoni AA, Wiese MD, Reeve E. Alterations in drug disposition in older adults: a focus on geriatric syndromes. Expert Opin Drug Metab Toxicol. 2021;17(1):41–52. doi:10.1080/17425255.2021.1839413

 PubMed Web of Science ®Google Scholar

Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvascular disease - systematic review and meta-analysis. Neurobiol Aging. 2009;30(3):337–352. doi:10.1016/j.neurobiolaging.2007.07.015

 PubMed Web of Science ®Google Scholar

van Assema DM, Lubberink M, Rizzu P, et al. Blood-brain barrier P-glycoprotein function in healthy subjects and Alzheimer’s disease patients: effect of polymorphisms in the ABCB1 gene. EJNMMI Res. 2012;2(1):57. doi:10.1186/2191-219X-2-57

 PubMed Web of Science ®Google Scholar

Hutchison LC, O’Brien CE. Changes in pharmacokinetics and pharmacodynamics in the elderly patient. J Pharm Prac. 2007;20:4–12. doi:10.1177/0897190007304657

 Google Scholar

Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol. 2004;57(1):6–14. doi:10.1046/j.1365-2125.2003.02007.x

 PubMed Web of Science ®Google Scholar

Trifirò G, Spina E. Age-related changes in pharmacodynamics: focus on drugs acting on central nervous and cardiovascular systems. Curr Drug Metab. 2011;12(7):611–620. doi:10.2174/138920011796504473

 PubMed Web of Science ®Google Scholar

Magnuson TM, Keller BK, Burke WJ. Extrapyramidal side effects in a patient treated with risperidone plus donepezil. Am J Psychiatry. 1998;155(10):1458–1459. doi:10.1176/ajp.155.10.1458a

 PubMed Web of Science ®Google Scholar

Spina E, Scordo MG, D’Arrigo C. Metabolic drug interactions with new psychotropic agents. Fundam Clin Pharmacol. 2003;17(5):517–538. doi:10.1046/j.1472-8206.2003.00193.x

 PubMed Web of Science ®Google Scholar

Carrier L. Donepezil and paroxetine: possible drug interaction. J Am Geriatr Soc. 1999;47(8):1037. doi:10.1111/j.1532-5415.1999.tb01306.x

 PubMed Web of Science ®Google Scholar

Finch A, Pillans P. P-glycoprotein and its role in drug-drug interactions. Aust Prescr. 2014;37:137–139. doi:10.18773/austprescr.2014.050

 Google Scholar

Takeuchi R, Shinozaki K, Nakanishi T, Tamai I. Local Drug-Drug Interaction of Donepezil with Cilostazol at Breast Cancer Resistance Protein (ABCG2) Increases Drug Accumulation in Heart. Drug Metab Dispos. 2016;44(1):68–74. doi:10.1124/dmd.115.066654

 PubMed Web of Science ®Google Scholar

Mehrpouya M, Ataei S, Nili-Ahmadabadi A. Potential drug interactions with cholinesterase inhibitors in Alzheimer patients: a guideline for Neurologists. J Appl Pharm Sci. 2017;7(1):223–226. doi:10.7324/JAPS.2017.70134

 Google Scholar

Johnell K, Fastbom J. Concurrent use of anticholinergic drugs and cholinesterase inhibitors: register-based study of over 700,000 elderly patients. Drugs Aging. 2008;25:871–877. doi:10.2165/00002512-200825100-00006

 PubMed Web of Science ®Google Scholar

Modi A, Weiner M, Craig BA, Sands LP, Rosenman MB, Thomas J. Concomitant use of anticholinergics with acetylcholinesterase inhibitors in Medicaid recipients with dementia and residing in nursing homes. J Am Geriatr Soc. 2009;57:1238–1244. doi:10.1111/j.1532-5415.2009.02258.x

 PubMed Web of Science ®Google Scholar

Walker C, Perks D. Do you know about donepezil and succinylcholine? Anaesthesia. 2002;57:1041. doi:10.1046/j.1365-2044.2002.00117.x

 PubMed Web of Science ®Google Scholar

Sánchez Morillo J, Demartini Ferrari A, Roca de Togores López A. Interacción entre donepezilo y bloqueantes musculares en la enfermedad de Alzheimer [Interaction of donepezil and muscular blockers in Alzheimer’s disease]. Rev Esp Anestesiol Reanim. 2003;50(2):97–100.

 PubMedGoogle Scholar

Gauthier S. Cholinergic adverse effects of cholinesterase inhibitors in Alzheimer’s disease: epidemiology and management. Drugs Aging. 2001;18(11):853–862. doi:10.2165/00002512-200118110-00006

 PubMed Web of Science ®Google Scholar

[No authors listed]. Bradycardia due to cholinesterase inhibitors: identify adverse effects and take them into account. Prescrire Int. 2011;20(115):95.

 PubMedGoogle Scholar

Carcenac D, Martin-Hunyadi C, Kiesmann M, Demuynck-Roegel C, Alt M, Kuntzmann F. Syndrome extrapyramidal sous donepezil [Extra-pyramidal syndrome induced by donepezil]. Presse Med. 2000;29(18):992–993.

 PubMed Web of Science ®Google Scholar

Shimizu S, Mizuguchi Y, Sobue A, Fujiwara M, Morimoto T, Ohno Y. Interaction between anti- Alzheimer and antipsychotic drugs in modulating extrapyramidal motor disorders in mice. J Pharmacol Sci. 2015;127(4):439–445. doi:10.1016/j.jphs.2015.03.004

 PubMed Web of Science ®Google Scholar

Galligan JJ, Burks TF. Cholinergic neurons mediate intestinal propulsion in the rat. J Pharm Exper Ther. 1986;238(2):594–598.

 PubMed Web of Science ®Google Scholar

Lewin MJ. Cellular mechanisms and inhibitors of gastric acid secretion. Drugs Today (Barc). 1999;35(10):743–752. doi:10.1358/dot.1999.35.10.561693

 PubMed Web of Science ®Google Scholar

Tavassoli N, Sommet A, Lapeyre-Mestre M, Bagheri H, Montrastruc JL. Drug interactions with Cholinesterase inhibitors: an analysis of the French pharmacovigilance database and a comparison of two national drug formularies (Vidal, British National Formulary). Drug Saf. 2007;30(11):1063–1071. doi:10.2165/00002018-200730110-00005

 PubMed Web of Science ®Google Scholar

Wooten JM. Pharmacotherapy considerations in elderly adults. South Med J. 2012;105(8):437–445. doi:10.1097/SMJ.0b013e31825fed90

 PubMed Web of Science ®Google Scholar

Delafuente JC. Understanding and preventing drug interactions in elderly patients. Crit Rev Oncol Hematol. 2003;48(2):133–143. doi:10.1016/j.critrevonc.2003.04.004

 PubMed Web of Science ®Google Scholar

Eshetie TC, Nguyen TA, Gillam MH, Kalisch Ellett LM. A narrative review of problems with medicines use in people with dementia. Expert Opin Drug Saf. 2018;17(8):825–836. doi:10.1080/14740338.2018.1497156

 PubMed Web of Science ®Google Scholar

Mallet L, Spinewine A, Huang A. The challenge of managing drug interactions in elderly people. Lancet. 2007;370(9582):185–191. doi:10.1016/S0140-6736(07)61092-7

 PubMed Web of Science ®Google Scholar

Micromedex® HealthCare Series (internet database) Version 2.0. Greenwood Village, Colorado: Thomson Healthcare Inc; 2013. Available from: http://www.micromedexsolutions.com. Accessed November 22, 2020.

 Google Scholar

Heikkilä T, Lekander T, Raunio H. Use of an online surveillance system for screening drug interactions in prescriptions in community pharmacies. Eur J Clin Pharmacol. 2006;62(8):661–665. doi:10.1007/s00228-006-0149-4

 PubMed Web of Science ®Google Scholar

Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother. 2007;41(4):674–680. doi:10.1345/aph.1H423

 PubMed Web of Science ®Google Scholar

Le Couteur DG, Robinson M, Leverton A, et al. Adherence, persistence and continuation with cholinesterase inhibitors in Alzheimer’s disease. Australas J Ageing. 2012;31(3):164–169. doi:10.1111/j.1741-6612.2011.00564.x

 PubMed Web of Science ®Google Scholar

Kröger E, Tatar O, Vedel I, et al. Improving medication adherence among community-dwelling seniors with cognitive impairment: a systematic review of interventions. Int J Clin Pharm. 2017;39(4):641–656. doi:10.1007/s11096-017-0487-6

 PubMed Web of Science ®Google Scholar

Renn BN, Asghar-Ali AA, Thielke S, et al. A Systematic Review of Practice Guidelines and Recommendations for Discontinuation of Cholinesterase Inhibitors in Dementia. Am J Geriatr Psychiatry. 2018;26(2):134–147. doi:10.1016/j.jagp.2017.09.027

 PubMed Web of Science ®Google Scholar

By the 2019 American Geriatrics Society Beers Criteria Update Expert Panel. American Geriatrics Society 2019 updated AGS Beers Criteria for potentially inappropriate medication use in older adults. J Am Geriatr Soc. 2019;67(4):674–694.

 PubMed Web of Science ®Google Scholar

Gustafsson M, Sjölander M, Pfister B, Schneede J, Lövheim H. Effects of Pharmacists’ Interventions on Inappropriate Drug Use and Drug-Related Readmissions in People with Dementia-A Secondary Analysis of a Randomized Controlled Trial. Pharmacy (Basel). 2018;6(1):7. doi:10.3390/pharmacy6010007

 PubMedGoogle Scholar

Elliott RA, Goeman D, Beanland C, Koch S. Ability of older people with dementia or cognitive impairment to manage medicine regimens: a narrative review. Curr Clin Pharmacol. 2015;10(3):213–221. doi:10.2174/1574884710666150812141525

 PubMed Web of Science ®Google Scholar

Corsonello A, Pedone C, Incalzi RA. Age-related pharmacokinetic and pharmacodynamic changes and related risk of adverse drug reactions. Curr Med Chem. 2010;17(6):571–584. doi:10.2174/092986710790416326

 PubMed Web of Science ®Google Scholar